Elsevier

Metabolism

Volume 92, March 2019, Pages 170-192
Metabolism

Pharmacotherapy of obesity: Available medications and drugs under investigation

https://doi.org/10.1016/j.metabol.2018.10.010Get rights and content

Highlights

  • Obesity is a chronic, multifactorial disease, initially managed with lifestyle modifications

  • Upon failure an FDA approved medication can be started based on patient comorbidities

  • Many novel anti-obesity agents are currently in clinical trials

  • Bariatric surgery studies highlight the role of gut-derived hormones in weight loss

  • Agents referring to gastrointestinal hormones will more likely reach the market

Abstract

Obesity is a chronic disease with a continuously rising prevalence that currently affects more than half a billion people worldwide. Energy balance and appetite are highly regulated via central and peripheral mechanisms, and weight loss triggers a homeostatic response leading to weight regain. Lifestyle and behavioral modifications are the cornerstones of obesity management; however, they often fail to achieve or sustain long-term weight loss. Pharmacotherapy added onto lifestyle modifications results in an additional, albeit limited, weight reduction. Regardless, this weight reduction of 5–10% conveys multiple cardiovascular and metabolic benefits. In this review, evidence on the food and drug administration (FDA)-approved medications, i.e., orlistat, lorcaserin, phentermine/topiramate, liraglutide and naltrexone/bupropion, is summarized. Furthermore, anti-obesity agents in the pipeline for potential future therapeutic use are presented.

Introduction

Obesity is a chronic, complex disease, characterized by excessive fat accumulation, which alters anatomy and physiology, thus resulting in unfavorable metabolic, biomechanical and psychosocial health consequences [1,2]. Obesity results from the interplay of genetic, epigenetic, biological, hormonal, microbial, behavioral, sociocultural, and environmental factors that disturb the balance between caloric intake and energy expenditure [3,4]. Body mass index (BMI) is the most practical diagnostic tool available, although it is a crude index, not distinguishing specific distribution of fat and lean body mass [5].

Four out of the ten leading causes of death in the United States (US), i.e., heart disease, cancer, cerebrovascular events and type 2 diabetes (T2D), are to a certain extent linked to obesity [6]. Indeed, obesity largely impacts health status through its associations with dyslipidemia, hypertension, metabolic syndrome, prediabetes and T2D, cardiovascular disease (e.g. coronary artery disease), nonalcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), female infertility and male hypogonadism, certain types of cancers (e.g. endometrial, colon, breast cancer), sleep disturbances, particularly obstructive sleep apnea (OSA), osteoarthritis, depression, and neurocognitive disorders (e.g. Alzheimer's disease) [[7], [8], [9], [10], [11], [12], [13], [14]]. Obesity accounts for an estimated 0.8–13.7 lost years of life, mainly due to cardiovascular disease, T2D and cancer, depending on the severity and age of onset of obesity [15,16].

Currently, one-third of the adult population in the US is overweight and another one-third has obesity [17]. Worldwide, an estimated 650 million adults are affected, rendering this disease an epidemic and a major public health concern [17]. Furthermore, approximately $190 billion are spent annually for direct and indirect health care costs related to obesity in the US [18]. Prevalence of obesity is estimated to climb to 44% by 2030 with major health, social and financial consequences [19].

Lifestyle (e.g. diet and exercise) and behavioral modifications are the cornerstones of the management of obesity, but they are difficult to achieve and to sustain [20]. If they fail, pharmacotherapy is added, when BMI ≥ 30 or BMI ≥ 27 and at least one cardiovascular risk factor exists (e.g. hypertension, hyperlipidemia, T2D) [21]. This review focuses on the pharmacologic management of adult obesity, summarizing food and drug administration (FDA)-approved medications for obesity (Table 1) and introducing the drugs currently in the pipeline. Orlistat is the only FDA-approved medication for long-term management of obesity that can be prescribed to adolescents >12, while phentermine can be used for short-term in individuals >16 years of age [22].

Section snippets

Mechanisms of Obesity and Targets of Anti-obesity Drugs

Energy balance, eating and appetitive behaviors are highly regulated by central and peripheral hormones and neuropeptides that act on multiple brain areas and peripheral organs (Fig. 1) [5,[23], [24], [25], [26]]. Several central nervous system (CNS) networks are implicated in the development and management of obesity in humans, including the hypothalamus, reward system, emotion and memory related brain areas along with attention related cortex and prefrontal cortex responsible for cognitive

Mechanism of Action

Phentermine hydrochloric (HCl) (Adipex-P®, Lomaira®), diethylpropion/amfepramone (Tenuate®, Tenuate dospan®), benzphetamine (Didrex®), and phendimetrazine (Bontril®, Prelu-2®) are oral noradrenergic agonists that suppress appetite. They have been approved only as short-term (<12 weeks) anti-obesity medications since the 1950s (1959, 1950, 1956, 1956, respectively), due to the lack of long-term data [28]. They all exert their appetite suppressant effects through interaction with biogenic amine

Anti-obesity Medications in the Pipeline

One of the goals of the ongoing research on anti-obesity medications is the development of more potent and more selective agents, thus multiplying effectiveness and reducing toxicity. Scientific endeavors are also focused on the discovery of novel molecules that act through different pathways than the existing drugs.

Closing Remarks

Years of research have shed light on the brain areas, pathways and molecules responsible for regulating energy balance and controlling eating and have led to progress in the management of obesity [31,[279], [280], [281]]. Lifestyle modification is the cornerstone of preventing and managing obesity, which has numerous health benefits; nevertheless, weight loss is difficult to achieve and possibly more difficult to maintain. Weight loss is followed by activation of energy balance and appetite

Acknowledgements

EP and AP are funded by the Stavros Niarchos Foundation and NP by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – 389891681 (PE 2431/2-1).

Disclosure Statement

The authors have no conflict of interest.

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